The Potential Connection between Molecular Changes and Biomarkers Related to ALS and the Development and Regeneration of CNS

Abstract

Neurodegenerative diseases are one of the greatest medical burdens of the modern age, being mostly incurable and with limited prognostic and diagnostic tools. Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by the loss of motoneurons, with a complex etiology, combining genetic, epigenetic, and environmental causes. The neuroprotective therapeutic approaches are very limited, while the diagnostics rely on clinical examination and the exclusion of other diseases. The recent advancement in the discovery of molecular pathways and gene mutations involved in ALS has deepened the understanding of the disease pathology and opened the possibility for new treatments and diagnostic procedures. Recently, 15 risk loci with distinct genetic architectures and neuron-specific biology were identified as linked to ALS through common and rare variant association analyses. Interestingly, the quantity of related proteins to these genes has been found to change during early postnatal development in mammalian spinal cord tissue (opossum Monodelphis domestica) at the particular time when neuroregeneration stops being possible. Here, we discuss the possibility that the ALS-related genes/proteins could be connected to neuroregeneration and development. Moreover, since the regulation of gene expression in developmental checkpoints is frequently regulated by non-coding RNAs, we propose that studying the changes in the composition and quantity of non-coding RNA molecules, both in ALS patients and in the developing central nervous (CNS) system of the opossum at the time when neuroregeneration ceases, could reveal potential biomarkers useful in ALS prognosis and diagnosis.

Keywords: ALS-related genes; CNS development; amyotrophic lateral sclerosis; neuroregeneration; non-coding RNAs; peripheral biomarkers.

Figure 1

Functional classification of the proteins identified by MS as differentially distributed in the opossum P5 and P18 spinal cords. Proteins were classified based on assumed molecular function (A), biological process (B), or protein class (C).

Figure 1

Functional classification of the proteins identified by MS as differentially distributed in the opossum P5 and P18 spinal cords. Proteins were classified based on assumed molecular function (A), biological process (B), or protein class (C).

Figure 2

Matching genes/proteins identified through the common and rare variant association analyses from ALS patients [16] and the proteomic analysis of developing opossum spinal cord [17].

Figure 3

mRNA–miRNA–lncRNA network visualization. Green rectangles represent genes (i.e., mRNA), blue ellipses represent miRNA, and gray diamonds represent lncRNA. Jagged connections between RNA nodes represent interactions confirmed in whole blood while dotted lines represent interactions in different tissues. RNA nodes with fewer than two connections were not retained for visualization.